The overall objective of this proposal is the development of new strategies for the construction of carbocyclic or heterocyclic systems. This new methodology will facilitate the synthesis of biologically active compounds, and moreover, provide routes to previously unsynthesized compounds. Two strategies will be examined. In the first strategy we will study application of the intramolecular Diels-Alder reaction in the synthesis of the potent hypocholesterolemic agents mevinolin and dihydromevinolin. These compounds cause a marked decrease in serum cholesterol in man by inhibiting the rate-limiting enzymatic step (HMG-CoA reductase) in the cholesterol biosynthetic pathway. It is hoped that these agents will be useful for the treatment of atherosclerosis. The exploitation of the Claisen-rearrangement-mediated approach to hetero- and carbocycles in natural product synthesis is the second major topic of the program. The targeted compounds are primarily comprised of medium-sized rings. For example, this reaction will play a fundamental role in the construction of: the seven-membered ring of antitumor guaianolides (desacetoxymatricarin); as well as the eight-membered ring of both steganicin, which possesses antileukemic activity, and the cytotoxic taxane class of compounds, specifically, taxinine. A novel entry to the cyclodecane framework of the germacranes, a class of sesquiterpenes with a wide range of biological activities, will be demonstrated in the synthesis of costunolide and tulipinolide. Utilization of this process in the synthesis of the heterocyclic, neuronal excitatory compound, Alpha-kainic acid, will also be examined. Also, extension of this methodology to the bridged bicycloalkane class of compounds with possible application to clovene, the antitumor compound quadrone and an alternate taxane strategy will be pursued.